Decoding the hallmarks of GLP-1RA weight-loss super-responders.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped obesity treatment, yet weight-loss outcomes remain highly uneven in real-world care. Using a federated biomedical platform, we analyzed 135 349 individuals treated with semaglutide and tirzepatide formulations and stratified them as "super responders" (>15% weight loss), "moderate responders" (5%-15% weight loss), "minimal weight-loss group" (<5% weight loss), and "weight regainers." Ozempic, Wegovy, Mounjaro, and Zepbound had similar proportions of patients classified as moderate responders, ranging from 40% to 42%. Rates of super responders were highest for Zepbound (34%), followed by Wegovy (26%), Mounjaro (24%), and Ozempic (10%). Among moderate and super responders, the average weight after 1 year of treatment was similar to the average weight approximately 10 and 20 years prior to treatment initiation, respectively. Compared with patients with minimal or moderate response, super responders were more likely to be younger (mean age 51 years versus 55 years), female (80% versus 58%-65%), and white (90% versus 80%). Baseline clinical characteristics enriched among super responders compared to the minimal response group included fibromyalgia (rate ratio [RR]: 0.2, = .002) and osteoarthritis (RR = 0.5, = .001) for Zepbound, and psoriasis (RR = 2.5, = .03) for Wegovy. These results highlight significant heterogeneity in weight trajectories following sustained exposure to a GLP-1RA therapy and identify factors associated with increased weight loss, likely reflecting a combination of biological, behavioral, and social factors. These insights motivate further prospective analyses to help guide the development of more tailored weight-loss intervention strategies.